CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Hematology Center of the Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, State Key Laboratory of Radiation Medicine and Radioprotection, Soochow University School of Medicine, Suzhou, China.
Nat Immunol. 2019 Apr;20(4):433-446. doi: 10.1038/s41590-019-0324-2. Epub 2019 Feb 25.
Cells use mitophagy to remove damaged or unwanted mitochondria to maintain homeostasis. Here we report that the intracellular bacterial pathogen Listeria monocytogenes exploits host mitophagy to evade killing. We found that L. monocytogenes induced mitophagy in macrophages through the virulence factor listeriolysin O (LLO). We discovered that NLRX1, the only Nod-like receptor (NLR) family member with a mitochondrial targeting sequence, contains an LC3-interacting region (LIR) and directly associated with LC3 through the LIR. NLRX1 and its LIR motif were essential for L. monocytogenes-induced mitophagy. NLRX1 deficiency and use of a mitophagy inhibitor both increased mitochondrial production of reactive oxygen species and thereby suppressed the survival of L. monocytogenes. Mechanistically, L. monocytogenes and LLO induced oligomerization of NLRX1 to promote binding of its LIR motif to LC3 for induction of mitophagy. Our study identifies NLRX1 as a novel mitophagy receptor and discovers a previously unappreciated strategy used by pathogens to hijack a host cell homeostasis system for their survival.
细胞利用线粒体自噬来清除受损或不需要的线粒体以维持体内平衡。在这里，我们报告细胞内细菌病原体李斯特菌利用宿主线粒体自噬来逃避杀伤。我们发现李斯特菌通过毒力因子溶血素 O（LLO）在巨噬细胞中诱导线粒体自噬。我们发现，NLRX1 是唯一具有线粒体靶向序列的 Nod-like 受体（NLR）家族成员，它包含一个 LC3 相互作用区域（LIR），并通过 LIR 直接与 LC3 相关联。NLRX1 及其 LIR 基序对于李斯特菌诱导的线粒体自噬是必不可少的。NLRX1 缺陷和使用线粒体自噬抑制剂都增加了线粒体产生的活性氧，从而抑制了李斯特菌的存活。在机制上，李斯特菌和 LLO 诱导 NLRX1 的寡聚化，以促进其 LIR 基序与 LC3 的结合，从而诱导线粒体自噬。我们的研究确定 NLRX1 为一种新的线粒体自噬受体，并发现了以前未被重视的病原体利用宿主细胞内稳态系统进行生存的策略。
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